The present invention relates to new 12,13-(pyranosyl)-indolo[2,3-a]pyrrolo[3,4-c]-carbazole and 12,13-(pyranosyl)-furo[3,4-c]indolo[2,3-a]carbazole compounds, and to pharmaceutical compositions containing them.
Anti-cancer therapeutic requirements call for the constant development of new cytotoxic agents, with the aim of obtaining medicaments that are both more active and better tolerated. The compounds of the present invention have, for example, anti-tumour properties, which makes them useful in the treatment of cancers.
Various chemical modifications have been made to the rebeccamycin or staurosporine structure with a view to improving the anti-tumour potential. Mention may be made, for example, of Patent Specifications WO 98/07433, WO 99/02532 and EP 602 597 which claim rebeccamycin compounds comprising structural modifications to the oside moiety of the molecule and to the substituents present in the hexacyclic system. The article published in  less than  less than Bioorganic and Medicinal Chemistry 1998, 6, 1597-1604 greater than  greater than  also describes such compounds having good cytotoxic activity.
In addition to the fact that the compounds of the invention are new, they have a surprising in vitro and in vivo activity that is superior to that observed hitherto. The compounds discovered by the Applicant accordingly have anti-tumour properties that make them particularly useful in the treatment of cancers.
More especially, the present invention relates to compounds of formula (I) 
wherein:
R1 and R2 which may be identical or different, each independently of the other represents a group of formula U-V wherein:
U represents a single bond or a linear or branched (C1-C6)alkylene chain, optionally substituted by one or more identical or different groups selected from halogen and hydroxy, and/or optionally containing one or more unsaturated bonds,
V represents a group selected from a hydrogen atom, a halogen atom, a cyano group, a nitro group, an azido group, a linear or branched (C1-C6)alkyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a hydroxy group, a linear or branched (C1-C6)alkoxy group, an aryloxy group, an aryl-(C1-C6)alkoxy group in which the alkoxy moiety is linear or branched, a formyl group, a carboxy group, an aminocarbonyl group, an NRaRb, xe2x80x94C(O)xe2x80x94T1, xe2x80x94C(O)xe2x80x94NRaxe2x80x94T1, xe2x80x94NRaxe2x80x94C(O)xe2x80x94T1, xe2x80x94Oxe2x80x94C(O)xe2x80x94T1, xe2x80x94C(O)xe2x80x94Oxe2x80x94T1, xe2x80x94Oxe2x80x94T2xe2x80x94NRaRb, xe2x80x94Oxe2x80x94T2xe2x80x94ORa, xe2x80x94Oxe2x80x94T2xe2x80x94CO2Ra, xe2x80x94NRaxe2x80x94T2xe2x80x94NRaRb, xe2x80x94NRaxe2x80x94T2xe2x80x94ORa, xe2x80x94NRaxe2x80x94T2xe2x80x94CO2Ra and an xe2x80x94S(O)nxe2x80x94Ra group, wherein:
Ra and Rb, which may be identical or different, each represents a group selected from a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group and an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, or
xe2x80x83Ra+Rb form together with the nitrogen atom carrying them a monocyclic heterocycle having from 5 to 7 ring members, optionally containing within the ring system a second hetero atom selected from oxygen and nitrogen, and optionally being substituted by a group selected from linear or branched (C1-C6)alkyl, hydroxy, linear or branched (C1-C6)alkoxy, amino, linear or branched (C1-C6)alkylamino and di-(C1-C6)alkylamino in which each alkyl moiety is linear or branched,
T1 represents a group selected from linear or branched (C1-C6)alkyl, aryl, aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched, and a linear or branched (C1-C6)alkylene chain substituted by a group selected from xe2x80x94ORa, xe2x80x94NRaRb, xe2x80x94CO2Ra, xe2x80x94C(O)Ra and xe2x80x94C(O)NRaRb wherein Ra and Rb are as defined hereinbefore,
T2 represents a linear or branched (C1-C6)alkylene chain,
n represents an integer from 0 to 2 inclusive,
G represents an oxygen atom or an NR3 group wherein R3 represents a group selected from a hydrogen atom, a linear or branched (C1-C6)alkyl group, an aryl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, a cycloalkyl group, a cycloalkyl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an xe2x80x94ORa group, an xe2x80x94NRaRb group, an xe2x80x94Oxe2x80x94T2xe2x80x94NRaRb group, an xe2x80x94NRaxe2x80x94T2xe2x80x94NRaRb group, a (C1-C6)hydroxyalkylamino group in which the alkyl moiety is linear or branched, a di((C1-C6)hydroxyalkyl)amino group in which each alkyl moiety is linear or branched, a xe2x80x94C(O)xe2x80x94Ra group, an xe2x80x94NHxe2x80x94C(O)xe2x80x94Ra group and a linear or branched (C1-C6)alkylene chain substituted by one or more identical or different groups selected from halogen atoms and the groups cyano, nitro, xe2x80x94ORa, xe2x80x94NRaRb, xe2x80x94CO2Ra, xe2x80x94C(O)Ra, (C1-C6)hydroxyalkylamino in which the alkyl moiety is linear or branched, di((C1-C6)hydroxyalkyl)amino in which each alkyl moiety is linear or branched, and xe2x80x94C(O)xe2x80x94NHRa, the groups Ra, Rb and T2 being as defined hereinbefore,
X represents a group selected from a hydrogen atom, a hydroxy group, a linear or branched (C1-C6)alkoxy group, a mercapto group and a linear or branched (C1-C6)alkylthio group,
Y represents a hydrogen atom, or
X and Y together with the carbon atom carrying them form a carbonyl group,
X1 represents a group selected from a hydrogen atom, a hydroxy group, a linear or branched (C1-C6)alkoxy group, a mercapto group and a linear or branched (C1-C6)alkylthio group.
Y1 represents a hydrogen atom, or
X1 and Y1 together with the carbon atom carrying them form a carbonyl group,
R4 and R5, which may be identical or different, each independently of the other represents a group selected from a hydrogen atom, a halogen atom, a hydroxy group, a linear or branched (C1-C6)alkoxy group, an aryloxy group, an aryl-(C1-C6)alkoxy group in which the alkoxy moiety is linear or branched, a linear or branched (C1-C6)alkyl group, an aryl-(C1-C6)alkyl group in which the alkyl moiety is linear or branched, an aryl group, an amino group (itself being optionally substituted by one or two identical or different groups selected from linear or branched (C1-C6)alkyl, aryl and aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched), an azido group, an xe2x80x94Nxe2x95x90NRa group (wherein Ra is as defined hereinbefore), and an xe2x80x94Oxe2x80x94C(O)xe2x80x94Rc group wherein Rc represents a linear or branched (C1-C6)alkyl group (optionally substituted by one or more groups selected from halogen, hydroxy, amino, linear or branched (C1-C6)alkylamino and di-(C1-C6)alkylamino in which each alkyl moiety is linear or branched), an aryl group, an aryl-(C1-C6)alkyl in which the alkyl moiety is linear or branched, a cycloalkyl group and a heterocycloalkyl group.
R6 represents a group of formula xe2x80x94U1-R4 wherein U1 represents a single bond or a methylene group, and R4 is as defined hereinbefore,
or R4, R5 and R6 taken in pairs in adjacent or non-adjacent positions form with the carbon atoms carrying them a ring system having from 3 to 6 ring members, containing one or two oxygen atoms, with the remaining group R4, R5 or R6 that does not belong to the ring system having any one of the definitions of R4, R5 or R6 given hereinbefore,
their isomers, and addition salts thereof with a pharmaceutically acceptable acid or base,
provided that the compounds of formula (I) are other than the following compounds:
1,11-dichloro-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione,
12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]-pyrrolo[3,4-c]carbazole-5,7-dione,
12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]-pyrrolo[3,4-c]carbazol-5-one, and
12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)-5,6,12,13-tetrahydro-(7H)-indolo[2,3-a]pyrrolo[3,4-c]-carbazol-7-one,
it also being understood that:
xe2x80x9ccycloalkylxe2x80x9d is understood to mean a monocyclic or bicyclic group that is saturated or unsaturated but without aromatic character, having from 3 to 10 carbon atoms, being optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)trihaloalkyl, hydroxy, linear or branched (C1-C6)alkoxy, and amino optionally substituted by one or two linear or branched (C1-C6)alkyl groups,
xe2x80x9cheterocycloalkylxe2x80x9d is understood to mean a cycloalkyl group as defined above having within the ring system one or two identical or different hetero atoms selected from oxygen, nitrogen and sulphur,
xe2x80x9carylxe2x80x9d is understood to mean a phenyl, naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or indanyl group, each of those groups being optionally substituted by one or more identical or different groups selected from halogen, linear or branched (C1-C6)alkyl, linear or branched (C1-C6)trihaloalkyl, hydroxy, linear or branched (C1-C6)alkoxy, and amino optionally substituted by one or two linear or branched (C1-C6)alkyl groups.
Among the pharmaceutically acceptable acids there may be mentioned by way of non-limiting example hydrochloric acid, hydrobromic acid, sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid, tart ric acid, maleic acid, citric acid, ascorbic acid, oxalic acid, methanesulphonic acid, camphoric acid, etc.
Among the pharmaceutically acceptable bases there may be mentioned by way of non-limiting example sodium hydroxide, potassium hydroxide, triethylamine, tert-butylamine, etc.
Advantageously, the preferred group G according to the invention is the group NR3 wherein R3 is as defined for formula (I).
According to an advantageous embodiment of the invention, the preferred compounds are those wherein X and Y together with the carbon atom carrying them form a carbonyl group, and X1 and Y1 together with the carbon atom carrying them form a carbonyl group.
According to another advantageous embodiment, the preferred compounds of the invention are the compounds of formula (I bis) 
wherein R1, R2, R3, R4, R5 and R6 are as defined for formula (I).
Preferably the substituents R1 and R2, which, according to the invention, may be identical or different, represent a group of formula U-V wherein U represents a single bond and V represents a group selected from a halogen atom, a hydrogen atom, a nitro group, a formyl group, a hydroxy group, and a linear or branched (C1-C6)alkylene chain substituted by a hydroxy group.
Especially advantageously the substituents R1 and R2 are identical.
The preferred substituents R3 according to the invention are the hydrogen atom, the hydroxy group and the linear or branched (C1-C6)alkylene chain substituted by a group selected from NRaRb and ORa wherein Ra and Rb are as defined for formula (I).
According to a final especially advantageous embodiment, the preferred compounds of the invention are the compounds of formula (I ter): 
wherein R1, R2, R3 and R6 are as defined for formula (I).
The preferred compounds according to the invention are:
3,9-diformyl-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione,
3,9-dinitro-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H])-indolo[2,3)-a]pyrrolo[3,4-c]carbazole-5,7-dione,
3-nitro-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione,
9-nitro-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione,
6-hydroxy-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione,
3,9-di-(hydroxymethyl)-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione,
3,9-dinitro-12,13-[1,2-(3,6-anhydro-4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione,
3,9-dihydroxy-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione,
3,9-dibromo-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione, and
6-diethylaminoethyl-12,13-[1,2-(4xe2x80x94O-methyl-xcex2-D-mannopyranosyl)]-6,7,12,13-tetrahydro-(5H)-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7-dione and its hydrochloride.
The isomers and addition salts with a pharmaceutically acceptable acid or base of the preferred compounds of the invention form an integral part of the invention.
The present invention relates also to a process for the preparation of compounds of formula (I), characterised in that there is used as starting material a compound of formula (II): 
wherein X, Y, X1. Y1, R4, R5 and R6 are as defined for formula (I),
which is treated in a basic medium with para-toluenesulphonic acid, to yield a compound of formula (III): 
wherein X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore,
which compound of formula (III) is reacted with sodium azide, to yield principally a compound of formula (I/a), a particular case of the compounds of formula (I): 
wherein X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore,
which compound of formula (I/a) is subjected to conditions of hydrogenolysis, to yield a compound of formula (I/b), a particular case of the compounds of formula (I): 
wherein X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore,
which compound of formula (I/b) is treated with aqueous sodium hydroxide solution and then treated With hydrochloric acid to yield a compound of formula (I/c), a particular case of the compounds of formula (I): 
wherein X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore,
which compound of formula (I/c) is subjected to the action of a compound of formula (IV):
R3axe2x80x94NH2xe2x80x83xe2x80x83(IV) 
wherein R3a has the same definitions as R3 with the exception of a hydrogen atom,
to yield a compound of formula (I/d), a particular case of the compounds of formula (I): 
wherein X, Y, X1, Y1, R3a, R4, R5 and R6 are as defined hereinbefore,
the totality of the compounds of formulae (I/b) to (I/d) constituting the compounds of formula (I/e): 
wherein G, X, Y, X1, Y1, R4, R5 and R6 are as defined for formula (I), which compound of formula (I/e) is subjected to an electrophilic aromatic addition reaction or to a nucleophilic aromatic addition reaction, according to conventional conditions of organic synthesis well known to the person skilled in the art, to yield a compound of formula (I/f), a particular case of the compounds of formula (I): 
wherein G, X, Y, X1, Y1, R4, R5 and R6 are as defined hereinbefore, and R1a and R2a have the same definitions as R1 and R2, respectively, except that R1a and R2a cannot simultaneously represent a hydrogen atom,
which compounds of formulae (I/a) to (I/f) constitute the totality of the compounds of formula (I), which are purified, if necessary, according to conventional purification techniques, which may, if desired, be separated into their different isomers according to a conventional separation technique, the substituents R4, R5 and R6 of which are adjusted according to conventional methods of organic synthesis used in the field of sugar chemistry, and which are converted, if desired, to addition salts thereof with a pharmaceutically acceptable acid or base.
The compounds of formulae (II) and (IV) are either commercial compounds or are obtained according to conventional methods of organic synthesis readily accessible to the person skilled in the art.
The compounds of formula (I) have especially valuable anti-tumour properties. They have excellent in vitro cytotoxicity on cell lines, and an action on the cell cycle. The characteristic properties of the compounds enable them to be used therapeutically as anti-tumour agents.
The present invention relates also to pharmaceutical compositions comprising as active ingredient at least one compound of formula (I), an optical isomer thereof, or an addition salt thereof with a pharmaceutically acceptable acid or base, on its own or in combination with one or more inert, non-toxic, pharmaceutically acceptable excipients or carriers.
Among the pharmaceutical compositions according to the invention, there may be mentioned more especially those that are suitable for oral, parenteral (intravenous, intramuscular or subcutaneous), per- or trans-cutaneous, nasal, rectal, perlingual, ocular or respiratory administration, and especially tablets or dragees, sublingual tablets, gelatin capsules, capsules suppositories, creams, ointments, dermal gels, injectable or drinkable preparations, aerosols, eye or nose drops, etc.
Owing to the characteristic pharmacological properties of the compounds of formula (I), pharmaceutical compositions comprising the said compounds of formula (I) as active ingredient are accordingly especially useful in the treatment of cancers.
The useful dosage varies according to the age and weight of the patient, the route of administration, the nature and severity of the disorder, and whether any associated treatments are being taken, and ranges from 0.5 mg to 500 mg in one or more administrations per day.
The following Examples illustrate the invention but do not limit it in any way. The starting materials used are known products or are prepared according to known procedures.
The structures of the compounds described in the Examples were determined according to the usual spectrophotometric techniques (infrared, nuclear magnetic resonance, mass spectrometry, etc.).